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Gene Therapy
Overview What is Familial hypercholesterolemia? ''' Familial hypercholesterolemia (FH) is a genetic disorder that is caused by a defect on chromosome 19. It is a loss of function mutation in one allele in the LDLR gene which encodes for a LDL receptor protein, commonly found in the liver. This defect makes the body unable to remove LDL cholesterol from the blood (NIH 2014). Because of this, it causes the patient to have high levels of LDL cholesterol.The patient is born with this disease and because of this they can start having heart attacks at an early age. There are two different genotypes of FH that are seen in people-heterozygous and homozygous. The heterozygotes seem to have 2x or 3x the amount of LDL cholesterol in their bodies than a normal, unaffected individual. In the homozygotes, they can have almost 4x to 10x the amount of LDL cholesterol in their system. '''What is cholesterol and what is the difference between "LDL" and "HDL" cholesterol? Cholesterol is a waxy substance that is found in all of our cells in our bodies. It helps the body make different hormones, vitamin D, and helps digest foods. But having too much cholesterol can cause plaque to build up in your arteries. This can lead to coronary heart disease which can lead to heart failure. LDL cholesterol stands for "low-density lipoprotiens" and HDL stands for "high-density lipoproteins". A good balance of both of these is required for normal body function. LDL cholesterol, often referred to as the "bad" cholesterol, can become stuck to your arteries and cause plaque build up. On the other hand, HDL cholesterol can shuttle cholesterol from other parts of the body to the liver where it can be recycled. Gene Therapy techniques Historical therapies for FH In the past, many people with Familial Hypercholesterolemia received liver transplants throughout their life to help lower the levels of cholesterol they had in their bodies. But because they needed to have a transplant liver, they had to be on immunosuppressants for the rest of their lives. This caused many problems with the patients immune system and therefore other therapies and cures have been researched. Present gene therapies & current remedies At the present time there are no real gene therapies for FH that have been approved. There is on-going research to find a gene therapy that will give the patient long term and sustained results. What is on the market right now are two drugs called Mipomersen and Lomitapide. These drugs are both classified as lipid-reducing agents. They have their drawbacks as well. Even though these drugs reduce the amount of LDL cholesterol a patient has in his/her system, this is not the preferred strategy. We need cholesterol to survive. An excess amount of cholesterol or not enough cholesterol can cause health problems. Another drawback is these drugs have been found to cause hepatosteatosis or fatty liver disease. This is the phenomena where there is fat present in one's liver. This can cause permanent damage and lead to scar tissue build up. This in turn can lead to organ failure or liver cancer. With gene therapy, scientists and doctors are hoping that patients can avoid these horrible side effects. At this time, researchers are looking into the use of different vectors that could be used in this gene therapy. The most promising vector is the adeno-associated virus or AAV8. A common problem with viral vectors is that they are thought to cause adverse affects in patients or cause disease.This virus has been researched thoroughly and is not known to cause disease. Another problem is that this vector's genome is only 4.8 kilobases long. This means that larger genes will not be able to fit into this small vector, so different cloning strategies must be implemented. In theory, this vector would be able to deliver properly functioning LDL receptors to the patient and no immunosuppressant drugs would be needed. This offers scientists and doctors a promise of stable, long term results with this gene therapy. References "Gene Therapy for Hypercholesterolemia: Sweet Dreams and Flying Machines", Huff, Murray W., Circulation Research, American Heart Association, 2014; 115: 542-545. doi: 10.1161/CIRCRESAHA.114.304800. Retrieved: October 13, 2014. "Gene therapy for Familial Hypercholesterolemia", Van Craeweld E. et. al, Curr Pharm Des. 2011;17(24):2575-91. PMID: 21774774. "Familial Hypercholesterolemia", Medicine Plus, National Institute of Health, Published May 5, 2014. Retrieved October 13, 2014. "What is Cholesterol?", National Heart, Lung and Blood Institute, National Institute of Health (NIH), Published September 2012. Retrieved October 13, 2014. "Adeno-associated Virus", Multiple Authors, Wikipedia, Retrieved October 13, 2014.